Abstract 989: Ascites in colorectal peritoneal carcinomatosis supersedes mutational status and other clinical variables as negative prognostic factor for CRS-HIPEC via EMT pathway
Authors: Josephine Hendrikson, Ying Liu, Qiu Xuan Tan, Joey Wee-Shan Tan, Gillian Ng, Clara Yieh Lin Chong, Chin Jin Seo, Jolene Si Min Wong, Claramae Shulyn Chia, Chin-Ann Johnny Ong
Journal: Cancer Research (2023)

Abstract Peritoneal metastasis in colorectal cancer, also known as colorectal peritoneal carcinomatosis (CPC), signifies poor prognosis for patients and is associated with worse prognosis compared to other sites of metastasis. Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in selected patients has been shown to improve survival. In this study, we aimed to identify potential prognostic factors to predict survival in CRS-HIPEC patients and explore the molecular mechanism implicated in CPC. Patient demographic and clinicopathological characteristics, including MSI status, RAS/RAF, TP53, and APC mutational status were collected from 70 CPC patients who underwent CRS-HIPEC procedure at National Cancer Centre Singapore. Synchronous peritoneal metastasis (median OS = 43.6 months, p=0.008) and the presence of ascites (median OS = 29.53 months, p=0.013) were linked to poorer overall survival. In comparison, no significant difference in OS was observed when stratifying for tumor mutational status. Multivariate analysis demonstrated that the presence of ascites was the most significant clinical prognostic factor in CPC (HR 3.097; 95% CI 1.18-8.12). To interrogate the role of ascites in the biology of CPC, we performed transcriptomic profiling of CPC and peritoneal mesothelial cell lines, and identified Epithelial-Mesenchymal Transition (EMT) pathway as a common signaling pathway enriched upon treatment with CPC ascites. Proteomics analysis of CPC ascites revealed that EMT-related proteins were highly abundant. Combining both analyses, we identified 5 putative prognostic targets (TNC, POSTN, LUM, THBS1 and MXRA5) that drive ascites-induced EMT process in CPC. Taken together, these findings suggest that careful consideration should be given to performing CRS-HIPEC in CPC patients with clinically observable ascites, as CRS-HIPEC alone is insufficient to improve survival and novel therapeutic strategies are required as an adjunct. The combination of transcriptomics and proteomics analysis of CPC ascites provides insights into the dynamic interactions between tumor cells and their microenvironment, which can be harnessed for identification of prognostic surrogate markers and future development of targeted therapy in CPC. In this study, we identified putative targetable targets driving ascites-induced EMT activation independent of the inherent molecular aberration in the CPC tumor. Citation Format: Josephine Hendrikson, Ying Liu, Qiu Xuan Tan, Joey Wee-Shan Tan, Gillian Ng, Clara Yieh Lin Chong, Chin Jin Seo, Jolene Si Min Wong, Claramae Shulyn Chia, Chin-Ann Johnny Ong. Ascites in colorectal peritoneal carcinomatosis supersedes mutational status and other clinical variables as negative prognostic factor for CRS-HIPEC via EMT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 989.